Daily Ards Research Analysis
A multi-cohort transcriptomic study identified circulating endothelial cell signatures that predict mortality and respiratory trajectories in adults with COVID-19 and in ventilated children, advancing non-invasive endothelial injury monitoring in ARDS contexts. Complementing this, a registered meta-analysis clarified major perinatal and clinical risk factors for bronchopulmonary dysplasia, and a multicenter cohort linked ABCA3 genotypes to prognosis, informing precision counseling in severe pedi
Summary
A multi-cohort transcriptomic study identified circulating endothelial cell signatures that predict mortality and respiratory trajectories in adults with COVID-19 and in ventilated children, advancing non-invasive endothelial injury monitoring in ARDS contexts. Complementing this, a registered meta-analysis clarified major perinatal and clinical risk factors for bronchopulmonary dysplasia, and a multicenter cohort linked ABCA3 genotypes to prognosis, informing precision counseling in severe pediatric interstitial lung disease.
Research Themes
- Non-invasive endothelial injury biomarkers predicting ARDS outcomes
- Risk stratification in neonatal chronic lung disease (BPD)
- Genotype–phenotype links in surfactant dysfunction (ABCA3) and prognosis
Selected Articles
1. Circulating endothelial signatures correlate with worse outcomes in COVID-19, respiratory failure and ARDS.
Using unsupervised deconvolution of blood transcriptomes, the authors quantified circulating endothelial cell signatures that were higher at baseline in non-survivors and independently associated with 28-day mortality. Elevated signatures also tracked worse respiratory trajectories, supporting a non-invasive biomarker of endothelial injury relevant to ARDS pathobiology.
Impact: Introduces a scalable transcriptomic metric of endothelial damage with prognostic value across pediatric and adult cohorts, bridging mechanism and risk stratification in ARDS-related respiratory failure.
Clinical Implications: ECS% could inform early risk stratification and trial enrichment for endothelial-targeted therapies in ARDS and severe COVID-19, enabling non-invasive monitoring of vascular injury.
Key Findings
- Baseline ECS% was higher in non-survivors vs survivors in adults with COVID-19 (2.9% vs 2.7%, n=932, p<0.001).
- Each 1% increase in baseline ECS% independently increased mortality risk (adjusted OR 1.36, 95% CI 1.03–1.79).
- In ventilated pediatric patients, day 0 ECS% was higher in non-survivors (2.8% vs 2.6%, n=244, p<0.05).
- Higher ECS% associated with worse respiratory trajectories across oxygen-requirement categories (p<0.001).
Methodological Strengths
- Multi-cohort validation spanning pediatric and adult populations with prospective registries (NCT01892969, NCT04378777).
- Novel unsupervised bulk-transcriptome deconvolution to quantify endothelial cell signatures.
Limitations
- Observational design limits causal inference and residual confounding may persist.
- Deconvolution-based ECS% depends on reference signatures and may vary across platforms and sample processing.
Future Directions: Prospective validation with predefined thresholds, integration into clinical decision-support, and biomarker-driven trials testing endothelial-targeted therapies in ARDS.
BACKGROUND: Elevated circulating endothelial cells (CECs), released from monolayers after insult, have been implicated in worse outcomes in ARDS and COVID-19, however there is no consensus proteomic phenotype that define CECs. We queried whether a transcriptomic approach would alternatively support the presence of endothelial cells in circulation and correlate with worsening respiratory failure. METHODS: To test whether elevated endothelial cell signatures (ECS) in circulation plays a role in worse respiratory outcomes, we used unsupervised bulk-transcriptome deconvolution to quantify ECS% in two cohorts. Our pilot analysis included pediatric patients requiring invasive mechanical ventilation (CAF-PINT, NCT01892969). Our validation cohort included adult hospitalized patients with COVID-19 (IMPACC, NCT04378777), testing the association of ECS% to outcomes in patients at risk of acute respiratory failure/ARDS. Primary outcome was 28-day mortality. RESULTS: In CAF-PINT, day 0 ECS% was higher in non-survivors compared to survivors of respiratory failure (2.8%, IQR 2.4-3.4% versus 2.6%, IQR 2.2-3.0% n = 244, p < 0.05, Wilcoxon rank-sum). In IMPACC, baseline ECS% (< 72 h of hospitalization) was higher in COVID-19 non-survivors versus survivors (2.9%, IQR 2.6-3.4%, versus 2.7%, IQR 2.3-3.1%, n = 932, p < 0.001, Wilcoxon rank-sum). Each 1% increase in baseline ECS% was significantly associated with mortality (adjusted OR 1.36, CI 1.03-1.79) by multivariable logistic regression. Increased baseline ECS% was associated with worse respiratory trajectories (2.5%, IQR 2.2-2.8% for trajectory with no oxygen requirements, 2.9%, IQR 2.6-3.4% for the trajectory with fatal outcome by day 28, n = 932, p < 0.001, one-way ANOVA). CONCLUSION: Quantifying ECS by deconvolution supports a transcriptomics-driven approach towards the non-invasive evaluation of endothelial damage in respiratory outcomes. This is a first step towards elucidating mechanistic components linking endothelial damage to ARDS utilizing non-invasive, circulating transcriptomic data by leveraging a novel deconvolution approach.
2. Risk factors for bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.
This PROSPERO-registered meta-analysis synthesized 23 studies (33,830 infants) and identified consistent perinatal and clinical risk factors for BPD, including chorioamnionitis, PROM, HDP, lower gestational age, male sex, SGA, prolonged ventilation/oxygen use, transfusion, PDA, sepsis, and RDS. The results refine risk stratification for prevention and early intervention.
Impact: Provides comprehensive, quantitatively robust estimates of BPD risk factors to guide perinatal risk stratification and quality-improvement targets.
Clinical Implications: Supports targeted prevention (e.g., infection control, minimizing invasive ventilation/oxygen exposure) and informs counseling for families of high-risk preterm infants.
Key Findings
- Chorioamnionitis and PROM increase BPD risk (OR 1.52 and 1.42, respectively).
- HDP is a strong maternal risk factor (OR 2.73).
- Lower GA (MD −1.86 weeks), male sex (OR 1.41), and SGA (OR 3.14) elevate risk.
- Prolonged MV (MD 16.55 days) and oxygen administration (MD 50.91 days) associate with BPD.
- PDA (OR 1.75), sepsis (OR 1.88), and RDS (OR 6.37) markedly increase risk.
Methodological Strengths
- PROSPERO registration and multi-database search with predefined criteria.
- Large aggregated sample enabling precise pooled estimates.
Limitations
- Heterogeneity in BPD definitions and clinical practices across included studies.
- Meta-analysis of observational data is subject to confounding and potential publication bias.
Future Directions: Standardize BPD definitions and exposures, develop multivariable risk scores, and test preventive bundles in prospective studies.
BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm infants. As medical advancements have increased the survival rate of preterm infants, the prevalence of BPD has also increased, representing a significant societal burden. The pathogenesis of BPD is multifactorial, involving both genetic and environmental factors. Although numerous studies have examined risk factors for BPD, their findings are inconsistent. Few meta-analyses exist, yet most focus on risk factors for the development of pulmonary hypertension in infants with BPD. The primary aim of this study was to identify the risk factors for BPD. METHODS: The study protocol was registered with PROSPERO (CRD42024616871). A comprehensive literature search was conducted in the PubMed, Embase, Cochrane Library, and Web of Science databases for case-control and cohort studies investigating risk factors for BPD. The search was completed on 22 November 2024, and the data were analyzed using Review Manager 5.3.5 and Stata 15.1. RESULTS: A total of 23 studies were included in the analysis, encompassing 14,729 patients in the bronchopulmonary dysplasia (BPD) group and 19,101 in the non-bronchopulmonary dysplasia (non-BPD) group. The meta-analysis revealed that chorioamnionitis (CA) was associated with an increased risk of BPD (OR = 1.52, 95% CI [1.23-1.87]), as was premature rupture of membranes (PROM; OR = 1.42, 95% CI [1.02-1.98]). Additionally, hypertensive disorders of pregnancy (HDP) were identified as a significant risk factor for BPD (OR = 2.73, 95% CI [1.31-5.69]). Other notable risk factors included lower gestational age (GA; MD = -1.86, 95% CI [-2.35 to -1.38]), male sex (OR = 1.41, 95% CI [1.14-1.75]), and being small for gestational age (SGA; OR = 3.14, 95% CI [1.03-9.60]). Furthermore, the analysis indicated that mechanical ventilation (MV; MD = 16.55, 95% CI [9.68-23.41]), oxygen administration (MD = 50.91, 95% CI [37.40-64.42]), and blood transfusion (OR = 1.38, 95% CI [1.06-1.81]) were significant risk factors for BPD. Other variables that were identified as significant risk factors included patent ductus arteriosus (PDA; OR = 1.75, 95% CI [1.35-2.27]), sepsis (OR = 1.88, 95% CI [1.44-2.46]), and respiratory distress syndrome (RDS; OR = 6.37, 95% CI [4.00-10.13]). CONCLUSIONS: Significant risk factors for BPD include CA, PROM, HDP, lower GA, male sex, SGA, MV, oxygen administration, blood transfusions, PDA, sepsis, and RDS. These findings hold potential clinical significance for predicting BPD pathogenesis.
3. Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort.
In a multicenter retrospective cohort of 36 children with ABCA3 variants, neonatal onset and pulmonary hypertension predicted poor outcomes, and genotype class strongly stratified survival. Null and NBD-involving variants conferred the worst prognosis, whereas missense variants outside NBD were enriched among longer-term survivors.
Impact: Provides clinically actionable genotype–phenotype correlations in a severe pediatric lung disorder, enabling precision prognosis and informing timing of advanced therapies.
Clinical Implications: Supports genotype-informed counseling, surveillance for pulmonary hypertension, and early consideration of advanced therapies (e.g., transplant) in high-risk genotypes.
Key Findings
- Among 36 children, 86% presented with neonatal respiratory distress; 75% died at median age 3 months; 5-year survival was 25%.
- Neonatal onset (p=0.009) and pulmonary hypertension (p=0.037) were associated with worse prognosis.
- Survival by genotype: null/null 0%, null/other 50%, other/other 23%; NBD-involving variants were particularly severe.
- Eight of 12 survivors beyond 1 year had at least one missense variant outside NBD or the hypomorphic p.Glu292Val.
Methodological Strengths
- Multicenter rare disease cohort with detailed genotype annotation over nearly three decades.
- Systematic genotype–phenotype analyses identifying clinically relevant risk strata.
Limitations
- Retrospective design with small sample size limits generalizability and control of confounding.
- Potential referral and survival biases across centers and over time.
Future Directions: Functional assays of specific variants, prospective registries with standardized care, and genotype-guided therapeutic trials in surfactant dysfunction.
BACKGROUND: ATP-binding cassette transporter A3 (ABCA3) deficiency is one of the most severe causes of childhood interstitial lung diseases (chILD). This study aims to report the RespiRare ABCA3 cohort and to establish phenotype-genotype correlations. METHODS: Phenotypic and genotypic data of patients under 18 years were retrospectively included (1995-2023) in the RespiRare centers. The initial presentation and evolution of the subjects was analyzed depending on their genotype. RESULTS: The ABCA3 cohort comprised 36 children (30 families), including 5.5%, 22%, and 72% of null/null (no protein), null/other (potential residual function) and other/other genotypes respectively. A neonatal respiratory distress syndrome was observed in 31 (86%) subjects and 27 (75%) died at a median age of 3 months. The 5-year overall survival was 25% with an overall median survival of 0.33 year (IQR 0.09-4.43). A neonatal onset (p = 0.009) and the presence of pulmonary hypertension (p = 0.037) impaired the prognosis. At the last follow-up, the survival rates were 0/2 (0%), 4/8 (50%) and 6/26 (23%) in the null/null, null/other and other/other groups respectively. Eight of the 12 subjects who survived beyond 1 year carried at least one missense variant outside the nucleotide-binding domains (NBD) (n = 9) or the hypomorphic p.(Glu292Val) variant (n = 1). CONCLUSION: The variable presentation and outcome of chILD due to ABCA3 pathogenic variants are linked to the underlying genotype. Neonatal onset, null variants, and variants involving the NBD are of peculiar severity.